Variant 3-193593380-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The NM_130837.3(OPA1):c.3G>A(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

OPA1
NM_130837.3 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 3.83

Variant links:

Genes affected

OPA1 (HGNC:8140): (OPA1 mitochondrial dynamin like GTPase) The protein encoded by this gene is a nuclear-encoded mitochondrial protein with similarity to dynamin-related GTPases. The encoded protein localizes to the inner mitochondrial membrane and helps regulate mitochondrial stability and energy output. This protein also sequesters cytochrome c. Mutations in this gene have been associated with optic atrophy type 1, which is a dominantly inherited optic neuropathy resulting in progressive loss of visual acuity, leading in many cases to legal blindness. [provided by RefSeq, Aug 2017]

OPA1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_130837.3 (OPA1) was described as [Likely_pathogenic] in ClinVar as 2504752

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-193593380-G-A is Pathogenic according to our data. Variant chr3-193593380-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1184499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-193593380-G-A is described in Lovd as [Likely_pathogenic]. Variant chr3-193593380-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPA1	NM_130837.3 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	1/31	ENST00000361510.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPA1	ENST00000361510.8 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	1/31	5	NM_130837.3	A1	O60313-10

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1395440

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

688144

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Genomics England Pilot Project, Genomics England

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 05, 2024

This sequence change affects the initiator methionine of the OPA1 mRNA. The next in-frame methionine is located at codon 125. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with autosomal dominant optic atrophy (PMID: 28125838, 31500643, 32141364, 34758253). ClinVar contains an entry for this variant (Variation ID: 1184499). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.46

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0059

T;.;.;T;T;.;T;.;.;.

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.90

D;D;D;D;.;D;D;D;D;D

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.62

MutationTaster

Benign

1.0

D;D;D;D;D;D

PROVEAN

Benign

-0.74

N;N;N;N;N;N;N;.;N;.

REVEL

Pathogenic

0.65

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;.;D;.

Sift4G

Benign

0.073

T;T;T;T;T;T;D;.;T;.

Polyphen

0.53

P;.;.;P;P;.;.;.;.;.

Vest4

0.87

MutPred

0.99

Loss of disorder (P = 0.076);Loss of disorder (P = 0.076);Loss of disorder (P = 0.076);Loss of disorder (P = 0.076);Loss of disorder (P = 0.076);Loss of disorder (P = 0.076);Loss of disorder (P = 0.076);Loss of disorder (P = 0.076);Loss of disorder (P = 0.076);Loss of disorder (P = 0.076);

MVP

0.97

ClinPred

1.0

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.94

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over